Toward Better Understanding of Isomorphism of Glycyrrhizic Acid and

Article pubs.acs.org/crystal

Toward Better Understanding of Isomorphism of Glycyrrhizic Acid and Its Mono- and Dibasic Salts Ewa Tykarska*,† and Maria Gdaniec*,§ †

Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland

§

S Supporting Information *

ABSTRACT: X-ray crystallography reveals that crystal structures of mono- and diammonium, mono- and dipotassium, and mono- and dicesium glycyrrhizinates are isomorphic, and they are also isomorphic with the earlier reported structure of glycyrrhizic acid. Despite differences in the ionization state of glycyrrhizic acid and the type and size of counterions, basic supramolecular organization in the crystals remains practically unchanged. The aggregation of amphiphilic glycyrrhizinate anions results in the structure with well separated hydrophobic (aglycone) and hydrophilic (diglucuronic unit, i.e., glycone) areas. In the glycyrrhizinate salts the hydrophilic area in the form of a flat two-dimensional platform consists of mono- or dideprotonated diglucuronic units arranged into zigzag chains. Solvent molecules and cations are an integral part of this hydrophilic area consolidating the platform by hydrogen bonds and ion−dipole interactions. Monovalent cations are located at the sites that in the glycyrrhizic acid structure are occupied by tetrahedrally hydrogen-bonded water molecules. Since they do not bind syn to the carboxylic or carboxylate groups of the diglucuronic units, the generation of the characteristic zigzag chains is possible, regardless of the ionization state of glycyrrhizic acid.

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INTRODUCTION The licorice (liquorice) herb is one of the most widely used medicinal plants since ancient times,1 and glycyrrhizic acid (GA) is considered the biologically active main ingredient of licorice root extract.2,3 Chemically, GA is a monodesmosidic saponin comprised of a triterpenoid hydrophobic aglycone (18βglycyrrhetinic acid) conjugated to a hydrophilic diglucuronic unit (Scheme 1). The pentacyclic triterpene is of β-amyrin type (oleanane), and the glycone contains two glucuronic acid residues. The amphiphilic structure of GA determines its physical properties in solution. Molecular aggregation of this surface-active compound in aqueous solution leads to the formation of aggregates, micelles and, at higher concentrations, a gel.4−7 As a polyprotic acid GA can exists in neutral or ionic forms with a varying degree of deprotonation. It is naturally occurring as a mixture of potassium and calcium salts,8 known as glycyrrhizin. This saponin exhibits a broad spectrum of pharmacological properties and has been the subject of an enormous amount of research.9−16 Recently, the interest in this natural compound has increased because of its ability to form water-soluble complexes with hydrophobic molecules.17−19 The effect of GA on the chemical stability, aqueous solubility, and bioavailability of drugs as well as the possibility of using this compound in a drug delivery system (DDS) is the subject of constant research.20−22 © 2013 American Chemical Society

Scheme 1

Received: December 2, 2012 Revised: January 18, 2013 Published: January 22, 2013 1301

dx.doi.org/10.1021/cg301768h | Cryst. Growth Des. 2013, 13, 1301−1308

Crystal Growth & Design

Article

Figure 1. Interdigitated layered structure of GA: (a) perspective drawing of a basic structural unit consisting of 2D sugar platform with triterpenoid moieties sticking out from both its sides; ball and stick (b) and space filling (c) representation showing channels formed by the interpenetrated basic units (molecules shown in light and dark gray belong to adjacent units). The channels consist ca. 42% of the crystal volume. In panels (a) and (b) hydrogen atoms have been omitted for clarity.

In the literature, structural information on GA, its salts, and its complexes is very limited. Only recently crystal structures of this important biologically active product have been reported revealing its supramolecular organization in the solid state.23,24 Surprisingly, the self-assembly mode of this triterpene glycoside seems to be invariant to the ionization state of the GA molecule, type of a counterion, or solvent used for crystallization. X-ray crystallography23 has revealed that conformation and crystal packing is practically identical for ionic and neutral forms of GA, and their aggregation leads to an interdigitated supramolecular layered architecture with alternating hydrophilic (glycone) and hydrophobic (aglycone) areas (Figure 1). In the hydrophobic parts there are intersecting channels filled with solvent or guest molecules. In turn, diglucuronic units connected via hydrogen bonds form a sugar platform with some solvent molecules and cations constituting an integral part of the sugar assembly. We have noticed that the structure of this sugar platform is such that replacement of the neutral GA molecule for its monobasic form occurs with minor structural reconstruction only. To obtain further insight into supramolecular organization of GA and its salts in the crystalline state, some new alkali and ammonium salts of GA have been prepared and their structures were determined by X-ray crystallography. Here we report the

crystal structures of mono- and dibasic ammonium, potassium, and cesium salts of GA that are, to a large extent, isomorphic with GA. To our knowledge this is very unusual and seldom the case that a polyprotic acid and its salts display isomorphism.25 We will try to explain how introduction of alkali metal and ammonium ions, accompanied by deprotonation of GA, can be accommodated without significant changes in the GA host crystal structure.

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EXPERIMENTAL SECTION

Monoammonium salt of GA and all reagents (analytical grade) were purchased from commercial suppliers and used without further purification. Elemental analyses were carried out by the Instrumentation Facility at the Faculty of Chemistry, Adam Mickiewicz University in Poznan. The tribasic salts of GA were prepared by a modified procedure described by Kondratenko et al.26 Single crystals of mono- and dibasic ammonium, potassium, and cesium GA salts were prepared by a slow evaporation method at room temperature and subjected to X-ray analysis. Crystals of monobasic salts were grown from carboxylic acid solutions (propionic or acetic acid), while their dibasic analogues were grown from DMF solutions. All studied crystals were highly solvated and very unstable in the air. They were also losing their diffracting power when kept in the mother liquor for a longer period of time (ca. two weeks). 1302



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Monoammonium Salt of GA (AGA). Single plate-like crystals of monoammonium salt of GA were grown from a 30 mM solution of AGA in 1:1 (v/v) H2O/propionic acid mixture. Diammonium Salt of GA (A2GA). The plate-like crystals of diammonium salt were obtained by slow evaporation of 10 mM solution of monoammonium salt of GA in a 1:1 (v/v) mixture of DMF and 25% aqueous ammonia. The crystals were dried under routine conditions (40 °C, 2 mmHg, 8 h, P2O5, KOH), established beforehand as safe in terms of decomposition and subjected to elemental analysis which pointed to the A2GA/DMF/H2O formula for the dried sample (found: C 56.75%, H 8.27% N 4.39%; calc.: C 57.01%, H 8.19%, N 4.43%). The crystals taken directly from the mother liquor were subjected to X-ray structural analysis that confirmed dibasic nature of the studied salt. Monopotassium Salt of GA (KGA). 5.0 mg of crude tripotassium salt of GA was dissolved in 200 μL of 50% aqueous acetic acid solution. Slow evaporation of this solution resulted in plate-like crystals of monopotassium salt. Dipotassium Salt of GA (K2GA). 2.7 mg of crude tripotassium salt of GA was dissolved in 400 μL of 1:3 (v/v) DMF/water mixture. Slow evaporation of this solution afforded plate-like crystals of dipotassium salt of GA. Monocesium Salt of GA (CsGA). 2.2 mg of crude tricesium salt of GA was dissolved in 150 μL of 30% aqueous propionic acid solution. Slow evaporation method resulted in the plate-like crystals of monocesium salt. Dicesium Salt of GA (Cs2GA). 5.5 mg of crude tricesium salt of GA was dissolved in 140 μL of 5:2 DMF/water mixture. Slow evaporation of this solution afforded plate-like crystals of dicesium salt of GA. Sodium and Lithium Glycyrrhizinates. Similar procedures were also applied to obtain sodium and lithium salts of GA; however these methods have yet to yield suitable crystals for structure determination. X-ray Structural Analyses. Intensity data for all crystals were collected at 130 K with an Oxford Diffraction SuperNova diffractometer using microsource and mirror-monochromated Cu Kα radiation and processed with the Agilent Technologies CrysAlis Pro software.27 The data were corrected for Lorentz and polarization factors and multiscan (AGA, A2GA, KGA, K2GA, CsGA) or Gaussian face index (Cs2GA) absorption corrections were applied. The structures were solved by direct methods and refined by full matrix least-squares on F2 (SHELXS-97 and SHELXL-97).28 For the refinement of A2GA Friedel pairs were merged. In all investigated crystal structures, except AGA, disorder of solvent molecules was observed. In a few cases restraints had to be imposed on the geometry and displacement parameters of the disordered molecules. In KGA and CsGA some disorder was also found in the part B (Scheme 1) of the GA glycone unit. In CsGA the cesium cation was disordered over two nearly equally occupied positions at a distance of 0.425 Å from each other. The C-bound hydrogen atoms were included in calculated positions and refined as riding on their parent atoms with Uiso(H) = 1.2Ueq(C) or 1.5Ueq for methyl groups. Hydrogen atoms of the ammonium ions were located in electron desity difference maps, the geometry of the ion approximated to tetrahedral with N−H distances of 0.90 Å. Whenever possible hydrogen atoms of the O−H groups were located in electron density difference maps, and their O−H distances were standardized to 0.84 Å. In some instances where hydrogen atoms could not be located in electron density difference maps, their positions were deduced by careful inspection of possible hydrogenbonding interactions. In a few cases of water molecules, due to disorder, hydrogen atom positions were not determined. In the final refinement cycles O−H hydrogen atoms were treated as riding on their parent atoms with Uiso(H) = 1.2Ueq(O). A summary of structure determination is given in Table 1. Geometry of hydrogen bonds is given in Tables S1−S6 (Supporting Information). The atom labeling of diglucuronic unit and GA molecule is shown in Figures 2 and S1 (Supporting Information).

Article

RESULTS AND DISCUSSION

GA is a polyprotic weak acid with pKa values of pKa1 = 3.98, pKa2 = 4.62, and pKa3 = 5.17 as recently reported.29 Synthesis of its salts is not straightforward. We have prepared mono- and dibasic potassium and cesium salts of GA from its tribasic salts adapting the published procedure for preparation of the tripotassium and trisodium salts of GA.26 Controlled hydrolysis of these salts in DMF/H2O solutions led to dibasic salts, whereas hydrolysis in propionic acid/H2O (for Cs+) or acetic acid/H2O (for K+) solution resulted in precipitation of monobasic salts. The diammonium salt was crystallized from DMF/ammonia solution with the monoammonium salt as a starting material. The X-ray crystallography of mono- and diammonium (AGA and A2GA), mono- and dipotassium (KGA and K2GA), and mono- and dicesium (CsGA and Cs2GA) salts of GA reveals that the crystal structures of GA23 and its mono- and dibasic salts are to a large extent isomorphous (Tables 1 and S11 Supporting Information). This result is somewhat unexpected taking into account different ionization states of the GA molecule as well as different character and ionic radii of the cations. The basic unit of supramolecular organization in all studied crystal structures is a 2D aggregate consisting of hydrogenbonded sugar platform and triterpenoid moieties protruding on its both sides. The partial interpenetration of such architectures results in alternating hydrophobic and hydrophilic areas (Figure 1). In GA and its mono- and dibasic salts, the triterpene carboxylic group is buried in a hydrophobic area. Its interaction mode with solvent molecules shows that this group plays the role of a hydrogen-bond donor and thus is neutral (Figure 3). The first acidic group to be deprotonated in GA is the carboxylic group of the glucuronic residue A (Scheme 1), the next one is the carboxylic group of the residue B, and the triterpene carboxylic group is the least acidic. X-ray structures show that the hydrophilic area of the crystal is able to accommodate neutral, mono-, and dibasic forms of GA together with the counterions, with a minimum degree of structural reconstruction. To illustrate it better and to explain the observed isomorphism of GA crystals, the construction of 2D sugar platform needs more detailed examination. Construction of 2D Sugar Platform. As shown in Figures 1 and 4 the hydrogen-bonded diglucuronic residues form a sugar platform that can be described as consisting of two layers shown in Figure 4 in green and blue. The basic motif within a single sugar layer is a polymeric zigzag chain consisting of hydrogen-bonded glycone units (Figure 4). There is no direct bonding between the chains from one layer. Instead, they are bridged by hydrogen bonds formed with diglucuronic units from antiparallel arranged chains belonging to the second layer. In effect, hollows in the form of hydrophilic pockets, surrounded by six diglucuronic units (M1−M6 in Figure 4b,c) from three adjacent chains, appear on both sides of a sugar platform. In the crystal structure of GA,23 this pocket accommodates three water molecules that bridge, via hydrogen bonds, different sugar chains thus consolidating the sugar platform. For the purpose of further discussion, the positions occupied by these water molecules are designated as sites I−III (Figure 2 and black spheres in Figure 4c). As can be seen in Figure 2 the water molecule located at site II is disordered over two positions, IIa and IIb, and, as will be shown later, these positions are characteristic for either monoor dibasic salts. 1303


b = 11.2823(3)

P212121 a = 10.6730(2) b = 11.1804(2)

P212121 a = 10.1563(3) b = 11.1999(5) c = 53.615(2)

orthorhombic

130

P212121

a = 10.6684(2)

b = 11.1245(1)

c = 51.3881(7)

crystal system

temperature, K

space group

unit cell dimensions, Å

1.296

calc density, g/cm3

1304

largest peak and hole, e A−3

R indices (all data)

1.05, −0.55 0.40,−0.38

R1 = 0.0440 wR2 = 0.1188

R1 = 0.0562 wR2 = 0.1557

R1 = 0.0552 0.62, −0.47

wR2 = 0.1180

wR2 = 0.1583

R1 = 0.0432

1.114

R1 = 0.0556

1.059

10451/2/788

wR2 = 0.1548

1.062

GOF on F2

9830/91/775

10451

32127

5.396

1.396

4

6153.4(2)

c = 51.567(1)

orthorhombic

1293.57

911598

R1 = 0.0548

10434/0/760

data/restraints/parameters

9830

16054

1.520

1.347

4

6098.7(4)

orthorhombic

1237.13

wR2 = 0.1577

10434

independent refl.

final R indices [I > 2σ(I)]

33519

refl collected

0.872

4

Z

absorption coefficient, mm

6098.8(2)

volume, Å3

−1

a = 9.8550(4)

130

130

1190.31

911597

911596

formula weight

A2GA

0.66, −0.38

wR2 = 0.1743

R1 = 0.0607

wR2 = 0.1727

R1 = 0.0595

1.056

5816/86/772

5816

14687

0.813

1.262

4

5855.0(5)

c = 52.659(3)

P212121

130

orthorhombic

1112.30

911599

C42H60O16(NH4)2·3DMF·2H2O

CCDC no.

CsGA C42H61O16Cs·3.79C2H5COOH·3.21H2O

KGA C42H61O16K·5.66CH3COOH·2.02H2O

AGA

C42H61O16NH4·3C2H5COOH·3H2O

empirical formula

Table 1. Crystal Data and Refinement Details for Monobasic and Dibasic Salts of GA K2GA

Cs2GA

0.83,−0.37

wR2 = 0.1434

R1 = 0.0508

wR2 = 0.1428

R1 = 0.0503

1.092

9768/0/731

9768

27632

2.099

1.326

4

5783.68(8)

1.18, −1.12

wR2 = 0.1340

R1 = 0.0490

wR2 = 0.1329

R1 = 0.0481

1.045

10437/10/707

10437

31208

9.927

1.483

4

6123.3(1)

c = 51.8388(6)

b = 11.4845(1)

c = 52.2345(2)

a = 10.2854(1)

b = 11.2520(1)

P212121

130

orthorhombic

1367.26

911601

C42H60O16Cs2·3DMF·3.4H2O

a = 9.8405(1)

P212121

130

orthorhombic

1154.42

911600

C42H60O16K2·3DMF·2H2O

Crystal Growth & Design Article



Article

Figure 2. The diglucuronic unit of GA showing three water molecules at sites I−III and atom labeling.23 R defines the triterpenoid fragment. Only one orientation of the carboxylic group of sugar B is shown.

Figure 3. The interaction modes of the carboxylic group of the GA aglycone and the propionic acid (top) or DMF (bottom) molecules.

Site I in GA and Its Monobasic Salts. In GA23 the water molecule occupying site I is involved in four tetrahedrally arranged hydrogen bonds, twice as an acceptor and twice as a donor of hydrogen bonds (Figure 5). In monoammonium salts of GA this site is occupied by NH4+ cation, and its surrounding has to adjust to the interaction requirements of the ammonium cation which is a 4-fold donor of hydrogen bonding (Figure 6a). Both the water molecule in GA and the ammonium ion in AGA link two different sugar chains from the same layer of the sugar platform by joining M1 with M4 (Figure 4c). A similar situation is observed in other monobasic salts where monovalent cations with ionic radii smaller (K+, 1.38 Å) or larger (Cs+, 1.67 Å) than NH4+ (1.50 Å) are also located at site I. The metal ions are eight- (K+) and nine-(Cs+) coordinated (Figure 6b,c), with K+O and Cs+O distances in the range 2.731(2)−2.961(2) Å and 3.003(3)−3.547(3) Å, respectively (Table S7 Supporting Information). The coordinating oxygen atoms originate primarily from the sugar platform; the potassium ion forms five contacts with three diglucuronic residues (M1, M4, M6), while the larger cesium ion bridges four residues (M1, M4−M6) via six bonds (Figure 6b,c). The remaining three metal−oxygen contacts are formed with the water molecule located at site IIb and two solvent carboxylic acid molecules. In monobasic alkali salts of GA, hydrogen bonds that were formed by the water molecule or ammonium ion located at site I are replaced by metal−ligand interactions, with some additional sugar and solvent O atoms entering the coordination

Figure 4. Structure of a sugar platform in GA: (a) side view down [010]; (b) top view down [001]; (c) the space-filling representation down [001] showing the hollows surrounded by six diglucuronic units M1−M6. The black spheres indicate positions of solvent molecules or cations at sites I−III. Dashed lines represent hydrogen bonds.

Figure 5. Hydrogen-bond interactions of water molecules located at sites I−III in the crystal structure of GA.23 M1−M6 denote diglucuronic units surrounding the hollow within the sugar platform (see Figure 4b,c). S1−S3 are the solvent molecules. 1305



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molecules at sites IIa and IIb in GA23 (Figure 5) exhibit a nearly tetrahedral arrangement with three groups bonded to both water molecules. The water molecule at site IIb, via the water molecule at site I, connects triterpenoid O3 atom with the residue A carboxylic group, while the water molecule at site IIa links O3 atom directly with the carboxylic group of sugar B. The latter interaction, as it will be shown by the structures of dibasic salts, restricts the rotation of the residue B carboxylate group around the C5B−C6B bond. In monobasic salts of GA the water molecule occupies exclusively site IIb (Figure 6) and therefore the carboxylic group of the residue B reveals some rotational freedom around the C5B−C6B bond, as reflected in the values of O5B−C5B−C6B−O6B torsion angle [55(2)− 159.2(6)°; see Table S10 Supporting Information]. These conformational differences result in alteration of the motifs formed by hydrogen-bonded diglucuronic units in the zigzag chain that has practically no impact on the remaining part of the crystal structure and basically requires only a minor reorientation of hydrogen bond donor−acceptor pattern (Figure 7a−c). Site I and II in Dibasic Salts of GA. In diammonium, dipotassium, and dicesium salts of GA one of the cations occupies site I, just as in monobasic salts, and the second one is always located at site IIa (Figure 8). Site IIb, which is closer to site I, is not occupied due to increased repulsive forces between positive charges. The distance between the two cations at sites I and IIa is 3.951(5), 4.051(1), and 4.2467(6) Å for diammonium, dipotassium, and dicesium salts, respectively. These cations are always bridged by the carbonyl O atom of the DMF molecule that is involved either in hydrogen bonds in diammonium salt or dipole−ion interactions in the case of the alkali salts (Figure 8). Another bridge is formed by glucuronic A residue through binding of the etheric O3 and O5A atoms to the cations at sites I and IIa. The coordination number of the alkali cation at site I is 7 and 8 for K+ and Cs+ respectively; i.e., it is reduced by one relative to the corresponding monocation analogue due to the absence of the water molecule at site IIb. The alkali cations at site IIa are always six-coordinated (Figure 8b,c, Table S8 Supporting Information). In contrast to the monobasic salts of GA, in its dibasic analogues the torsion angles O5B−C5B−C6B−O6B, characterizing the twist of the carboxylate group relative to the residue B pyranose ring, have similar values [123.0(7)−136.0(3)°, Table S10 Supporting Information] because the ions at site IIa bridge the O3 and O7B atoms restricting rotation of this carboxylate group. Thus, in dibasic salts of GA only one motif of association between diglucuronic units within the polymeric zigzag chain has been found (Figure 7d). Both ions (I and IIa) fit into the hollow formed by six diglucuronic units, but the occupied postions slightly differ owing to the variation in ionic radii and different nature of the interactions between cations and surrounding oxygen atoms. The sugar platform accommodates these changes by shifting cations in the direction approximately perpendicular to its surface. Thus, smaller K+ ions are buried deeper in the sugar platform than larger Cs+ ions (Table S9 Supporting Information). In turn, in the diammonium salt the NH4+ cations exhibit two extreme positions, with the ion at site I showing the maximum shift out of the platform and that at site IIa the maximum shift toward the platform interior. An important feature of the cation binding at site IIa is that it does not bind syn to the carboxylate oxygen atoms leaving syn position for hydrogen bonding interactions and allowing thus for generation of zigzag chains in the sugar platform. All together deprotonation of the carboxylic

Figure 6. Hydrogen-bond or dipole−ion interactions of cations located at sites I and hydrogen-bond interactions of solvent molecules at sites IIb and III in monobasic salts: (a) AGA, (b) KGA, (c) CsGA. M1−M6 denote diglucuronic units surrounding the hollow within the sugar platform (see Figure 4b,c). S1−S3 are the solvent molecules.

sphere of the cation which leads to a better consolidation of the hydrophilic area. This is reflected in the shift of the metal ions toward the interior of the sugar platform in comparison to the tetrahedrally surrounded water molecule or NH4+ ion (Table S9 Supporting Information). As illustrated above, within the series of GA compounds site I can be occupied by H2O, NH4+, K+, or Cs+, i.e., molecules or ions with their radii in a certain range, forming different types of interactions with surrounding atoms. Site II in GA and Its Monobasic Salts. The hydrogen-bond donor and acceptor groups surrounding the disordered water 1306



Article

Figure 8. Hydrogen-bond and dipole−ion interactions of cations located at sites I and IIa and hydrogen-bond interactions of solvent molecules at site III in dibasic salts: (a) A2GA, (b) K2GA, (c) Cs2GA. M1−M6 denote diglucuronic units surrounding the hollow within the sugar platform (see Figure 4b,c). S1−S3 are the solvent molecules.

Figure 7. Motifs generated by the hydrogen-bonded diglucuronic units in the zigzag chains in mono- and dibasic salts of GA: (a) KGA; (b) AGA crystallized from methanol;23 (c) AGA and CsGA; (d) A2GA, K2GA, and Cs2GA.

from the same layer, acting both as an acceptor and as a donor of hydrogen bonding (Figures 5, 6, and 8). Isomorphism of GA and Its Mono- and Dibasic Monovalent salts. As shown by X-ray crystallography the crystal structures of GA and its salts are to a large extent isomorphic. They crystallize in P212121 space group with the unit cell parameters in the following ranges: a = 9.8405(1)− 10.6730(2) Å, b = 11.1804(2)−11.4845(1) Å, and c = 50.3536(6)− 53.615(2) Å (Tables 1 and S11 Supporting Information). In all

group of the glucuronic B residue and simultaneous addition of another alkali cation retains the construction of interdigitated supramolecular layered architecture practically intact when compared with the structure of GA and monobasic analogues. Site III in GA and Its Mono- and Dibasic Salts. In all investigated structures, at site III of the sugar platform the OH groups from water, methanol23 or carboxylic acid molecules have been found. These groups bridge the parallel zigzag chains 1307



Article

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dibasic salts the unit-cell parameter a is shorter than this parameter in the monobasic analogue. This shortening results from contraction of the sugar zigzag chain in the dibasic salt due to additional bridge formed between diglucuronic units M1 and M2 by an ion located at site IIa (Figure 8). The isomorphism of GA and its mono- and dibasic salts suggests that formation of isomorphous crystals containing nonstoichiometric amount of cations as well as GA in different deprotonation states cannot be ruled out. Our preliminary results confirm that the crystals formed in certain conditions contained more than 1 and less than 2 potassium cations per one GA unit. The main factor leading to isomorphism of GA and its mono- and dibasic salts is certainly connected to the construction of a sugar platform. The minor reconstruction of hydrogen bond network that occurs with the change of deprotonation state of carboxylic groups is facilitated by a dual hydrogen-bond donor−acceptor nature of hydroxy groups. Moreover, construction of the platform allows for replacement of the neutral solvent molecules that form an integral part of the platform by monovalent cations.

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CONCLUSION Reported here are crystal structures of monobasic and dibasic salts of GA with monovalent ammonium and alkali K+ and Cs+ cations reveal a strong tendency of these salts to form isomorphic crystals. Isomorphism extends also to the GA structure.23 We have found that the main reason for the observed isomorphism is a specific structure of hydrophilic bilayers assembled from zigzag chains of neutral, monoanionic, or dianionic diglucuronic units. These bilayers, via minor reconstruction of their hydrogenbond network, are able to accommodate changes resulting from the different ionization states of GA. Moreover, the counterions like ammonium, potassium, or cesium are able to replace tetrahedrally hydrogen-bonded water molecules that are an integral part of the sugar platform in the crystal structure of GA.23 Thus, the chemical diffreneces between GA and its mono- and dibasic salts practically have no impact on supramolecular organization of neutral and ionic forms of GA.

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ASSOCIATED CONTENT

S Supporting Information *

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Hydrogen-bond tables, cationO distances, atom labeling system and crystallographic information files (CIF). This material is available free of charge via the Internet at http:// pubs.acs.org.

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NOTE ADDED AFTER ISSUE PUBLICATION Table 1 was misformatted (and cut off) in the PDF version when the final issue was published on March 6, 2013 (Cryst. Growth Des. 2013, 13(3), 1301−1308). Table 1 is now corrected in this online version published on March 22, 2013. An accompanying addition/correction (DOI: 10.1021/cg4003884) was also published.

AUTHOR INFORMATION

Corresponding Author

*(E.T.) E-mail: [email protected]; fax: +48 61 8546639; tel: +48 61 8546632. (M.G.) [email protected]; tel: +48 61 8291273. Notes

The authors declare no competing financial interest.

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REFERENCES

(1) Fiore, C.; Eisenhut, M.; Ragazzi, E.; Zanchin, G.; Armanini, D. J. Ethnopharmacol. 2005, 99, 317−324. (2) Fenwick, G. R.; Lutomski, J.; Nieman, C. Food Chem. 1990, 38, 119−143. (3) Roshan, A.; Verma, N. K.; Kumar, Ch. S.; Chandra, V.; Singh, D. P.; Panday, M. K. Int. Res. J. Pharm. 2012, 3, 45−55. (4) Azaz, E.; Segal, R. Pharm. Acta Helv. 1980, 55, 183−186. 1308


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